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Parainfluenza virus types 1–4 (PIV1–4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1–4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.

Wheezing is a major problem in children, and respiratory viruses are often believed to be the causative agent. While molecular detection tools enable identification of respiratory viruses in wheezing children, it remains unclear if and how these viruses are associated with wheezing. The objective of this systematic review is to clarify the prevalence of different respiratory viruses in children with wheezing. We performed an electronic in Pubmed and Global Index Medicus on 01 July 2019 and manual search. We performed search of studies that have detected common respiratory viruses in children ≤18 years with wheezing. We included only studies using polymerase chain reaction (PCR) assays. Study data were extracted and the quality of articles assessed. We conducted sensitivity, subgroup, publication bias, and heterogeneity analyses using a random effects model. The systematic review included 33 studies. Rhinovirus, with a prevalence of 35.6% (95% CI 24.6-47.3, I2 98.4%), and respiratory syncytial virus, at 31.0% (95% CI 19.9-43.3, I2 96.4%), were the most common viruses detected. The prevalence of other respiratory viruses was as follows: human bocavirus 8.1% (95% CI 5.3-11.3, I2 84.6%), human adenovirus 7.7% (95% CI 2.6-15.0, I2 91.0%), influenza virus6.5% (95% CI 2.2-12.6, I2 92.4%), human metapneumovirus5.8% (95% CI 3.4-8.8, I2 89.0%), enterovirus 4.3% (95% CI 0.1-12.9, I2 96.2%), human parainfluenza virus 3.8% (95% CI 1.5-6.9, I2 79.1%), and human coronavirus 2.2% (95% CI 0.6-4.4, I2 79.4%). Our results suggest that rhinovirus and respiratory syncytial virus may contribute to the etiology of wheezing in children. While the clinical implications of molecular detection of respiratory viruses remains an interesting question, this study helps to illuminate the potential of role respiratory viruses in pediatric wheezing. PROSPERO, CRD42018115128.

We reported previously that the dominant receptors of influenza A and B viruses, and human and murine respiroviruses, were sialylglycoproteins and gangliosides containing monosialo-lactosamine type I-and II-residues, such as sialic acid-alpha2-3(6)-Galbeta1-3(4)-GlcNAcbeta1-. In addition, the Siaalpha2-3Gal linkage was predominantly recognized by avian and horse influenza viruses, and human parainfluenza virus type 1 (hPIV-1), whereas the Siaalpha2-6Gal linkage was mainly recognized by human influenza viruses (Paulson JC in \"The Receptors'' [Conn M Ed] 2, 131-219 (1985); Suzuki Y, Prog Lipid Res 33, 429-57 (1994); Ito T, J Virol 73, 6743-51 (2000); Suzuki Y, J Virol 74, 11825-31 (2000); Suzuki T, J. Virol 75, 4604-4613 (2001); Suzuki Y, Biol. Pharm. Bull. 28, 399-408 (2005)). To clarify the distribution of influenza virus receptors on the human bronchial epithelium cell surface, we investigated a primary culture of normal human bronchial epithelial (NHBE) cells using two types of lectin (MAA and SNA), which recognize sialyl linkages (alpha2-3 and alpha2-6), using fluorescence-activated cell-sorting analysis. The results showed that both alpha2-3- and alpha2-6-linked Sias were expressed on the surface of primary human bronchial epithelial cells. The cells infected by hPIV-1 bound to MAA, confirming that cells targeted by hPIV-1 have alpha2-3-linked oligosaccharides. We also compared the ability of hPIV-1 and human influenza A virus to infect primary human bronchial epithelial cells pre-treated with Siaalpha2-3Gal-specific sialidase from Salmonella typhimurium. No difference was observed in the number of sialidase pre-treated and non-treated cells infected with human influenza A virus, which binds to Siaalpha2-6Gal-linked oligosaccharides. By contrast, the number of cells infected with hPIV-1 decreased significantly upon sialidase treatment. Thus, cultured NHBE cells showed both alpha2-3-linked Sias recognized by hPIV-1 and avian influenza virus receptors, and alpha2-6-linked Sias recognized by human influenza virus receptors.

Background Human parainfluenza viruses (HPIVs) are important causes of upper respiratory tract illness (URTI) and lower respiratory tract illness (LRTI). To analyse epidemiologic and clinical characteristics of the four types of human parainfluenza viruses (HPIVs), patients with acute respiratory tract illness (ARTI) were studied in Guangzhou, southern China. Methods Throat swabs (n=4755) were collected and tested from children and adults with ARTI over a 26-month period, and 4447 of 4755 (93.5%) patients’ clinical presentations were recorded for further analysis. Results Of 4755 patients tested, 178 (3.7%) were positive for HPIV. Ninety-nine (2.1%) samples were positive for HPIV-3, 58 (1.2%) for HPIV-1, 19 (0.4%) for HPIV-2 and 8 (0.2%) for HPIV-4. 160/178 (88.9%) HPIV-positive samples were from paediatric patients younger than 5 years old, but no infant under one month of age was HPIV positive. Seasonal peaks of HPIV-3 and HPIV-1 occurred as autumn turned to winter and summer turned to autumn. HPIV-2 and HPIV-4 were detected less frequently, and their frequency of isolation increased when the frequency of HPIV-3 and HPIV-1 declined. HPIV infection led to a wide spectrum of symptoms, and more “hoarseness” (p=0.015), “abnormal pulmonary breathing sound” (p<0.001), “dyspnoea” (p<0.001), “pneumonia” (p=0.01), and “diarrhoea” (p<0.001) presented in HPIV-positive patients than HPIV-negative patients. 10/10 (100%) HPIV-positive adult patients (≥14 years old) presented with systemic influenza-like symptoms, while 90/164 (54.9%) HPIV-positive paediatric patients (<14 years old) presented with these symptoms (p=0.005). The only significant difference in clinical presentation between HPIV types was “Expectoration” (p<0.001). Co-infections were common, with 33.3%–63.2% of samples positive for the four HPIV types also testing positive for other respiratory pathogens. However, no significant differences were seen in clinical presentation between patients solely infected with HPIV and patients co-infected with HPIV and other respiratory pathogens. Conclusions HPIV infection led to a wide spectrum of symptoms, and similar clinical manifestations were found in the patients with four different types of HPIVs. The study suggested pathogenic activity of HPIV in gastrointestinal illness. The clinical presentation of HPIV infection may differ by patient age.

Human parainfluenza virus type 1 (HPIV-1), a paramyxovirus, is a leading cause of pediatric respiratory hospitalizations globally. Currently, there is no clinically successful vaccine against HPIV-1. Hence, there is a need to characterize circulating strains of this virus to establish the feasibility of developing a vaccine against the virus. The variable HPIV-1 hemagglutin–neuraminidase (HN) protein is found in the envelope of HPIV-1, where it initiates the infection process by binding to cellular receptors. HN is also the major antigen against which the human immune response is directed against. The present study focused on identifying mutations in the HN gene that would be useful in understanding the evolution of HPIV-1. 21 HPIV-1 isolates were obtained after screening nasopharyngeal samples from patients with influenza-like illness. The samples were collected from Mbagathi District Hospital Nairobi from the period July 2007 to December 2010. RT-PCR was carried out on the isolates using HN-specific primers to amplify a 360 nt in the most polymorphic region and the amplicons sequenced. Genomic data were analysed using a suite of bioinformatic software. Forty eight polymorphic sites with a total of 55 mutations were identified at the nucleotide level and 47 mutations at 23 positions at the amino acid level. There was more radical nonsynonymous amino acid changes (seven positions) observed than conservative nonsynonymous changes (one position) on the HN gene fragment. No positively selected sites were found in the HN protein. The result from the analysis of 21 HPIV-1 Mbagathi isolates demonstrated that the HN gene which is the major antigenic target was under purifying (negative) selection displaying evolutionary stasis.

Wheezing is a common problem in children under five with acute respiratory infections (ARIs). Viruses are known to be responsible for a considerable proportion of ARIs in children. This study was undertaken to know the viral aetiology of wheezing among the children less than five years of age, admitted to a tertiary care hospital in eastern India. Seventy five children, under the age of five years admitted with wheezing, were included in the study. Throat and nasal swabs were collected, and real-time multiplex polymerase chain reaction (PCR) assay was used to screen for influenza 1 and 2, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1, 2, 3 and 4, rhinovirus, human meta-pneumovirus, bocavirus (HBoV), Coronavirus, adenovirus, Enterovirus and Parechovirus. The total viral detection rate was 28.57 per cent. Viral RNA markers were detected from children diagnosed to be having pneumonia (3 cases), bronchiolitis (9 cases), episodic wheeze (2 cases) and multitrigger wheeze (6 cases). RSV was the most common virus (35%) followed by PIV1, 2 and 3 (20%), HBoV (10%) and rhinovirus (5%). However, mixed infection was observed in 30 per cent of cases. The study reported the presence of respiratory viral agents in 28.57 per cent of children with wheezing; RSV and PIV were most common, accounting to 55 per cent of the total cases. Mixed infection was reported in 30 per cent of cases. Seasonal variation in the occurrence of these viruses was also noted. Further studies need to be done with a large sample and longer follow up period to verify these findings.

Thirty-nine human parainfluenza type 1 (HPIV-1) genomes were sequenced from samples collected in Milwaukee, Wisconsin from 1997-2010. Following sequencing, phylogenetic analyses of these sequences plus any publicly available HPIV-1 sequences (from GenBank) were performed. Phylogenetic analysis of the whole genomes, as well as individual genes, revealed that the current HPIV-1 viruses group into three different clades. Previous evolutionary studies of HPIV-1 in Milwaukee revealed that there were two genotypes of HPIV-1 co-circulating in 1991 (previously described as HPIV-1 genotypes C and D). The current study reveals that there are still two different HPIV-1 viruses co-circulating in Milwaukee; however, both groups of HPIV-1 viruses are derived from genotype C indicating that genotype D may no longer be in circulation in Milwaukee. Analyses of genetic diversity indicate that while most of the genome is under purifying selection some regions of the genome are more tolerant of mutation. In the 40 HPIV-1 genomes sequenced in this study, the nucleotide sequence of the L gene is the most conserved while the sequence of the P gene is the most variable. Over the entire protein coding region of the genome, 81 variable amino acid residues were observed and as with nucleotide diversity, the P protein seemed to be the most tolerant of mutation (and contains the greatest proportion of non-synonymous to synonymous substitutions) while the M protein appears to be the least tolerant of amino acid substitution.

Human parainfluenza viruses (hPIVs) are major contributors to respiratory tract infections in young children worldwide. Despite their global significance, genomic surveillance of hPIV1 and hPIV2 had not previously been conducted in Russia. This study aimed to develop a robust amplicon-based sequencing protocol for these viruses. The designed primer sets were tested on clinical samples containing hPIV RNA to evaluate their performance and efficiency. Sequencing results demonstrated high-quality genome data and efficient amplification across various Ct values. As a result, 41 hPIV1 and 13 hPIV2 near-complete genome sequences were successfully obtained from clinical specimens collected in Saint Petersburg (Russia). Phylogenetic analysis of the HN gene sequences showed that Russian hPIV1 strains clustered into clades II and III, while hPIV2 strains were distributed between clusters G1a and G3. The whole-genome-based trees confirmed the same distribution of the strains. These findings highlight the potential of our primer panels and contribute to a better understanding of the molecular characteristics and phylogenetic diversity of circulating hPIV strains. Notably, this study presents the first evolutionary analysis of hPIVs in Russia.

This study investigated the long-term trends in human parainfluenza virus (HPIV) types 1, 2, and 3 in Korea by year, age group, and season. A total of 23,284 nasopharyngeal swabs collected from patients with respiratory symptoms at a tertiary hospital in Korea between 2007 and 2024 were tested for HPIV using real-time reverse-transcription polymerase chain reaction. Of the 23,284 specimens tested, 481 were positive for HPIV-1, 164 for HPIV-2, and 1102 for HPIV-3. HPIV-3 showed the highest incidence between 2010 and 2016, a decline after 2018, a sharp decline during the 2020 COVID-19 pandemic, and a resurgence in 2021. HPIV-1 and HPIV-2 incidence fluctuated between 2007 and 2019, followed by a sharp decline in 2020. HPIV-3 activity peaked in spring and summer, whereas HPIV-1 and HPIV-2 peaked in autumn. For all three types, infection rates were generally highest among children aged 1–12 years, followed by those in infants, but infection rates varied significantly by type, year, season, and age group. These findings emphasize targeted pediatric prevention, predictive modeling of seasonal peaks, and continued molecular surveillance to clarify the genetic and antigenic diversity of HPIV types after the pandemic, supporting the Sustainable Development Goals (SDG 3 for Good Health and Well-Being).

Background Reducing acute respiratory infection burden in children in Africa remains a major priority and challenge. We analyzed data from population-based infectious disease surveillance for severe acute respiratory illness (SARI) among children <5 years of age in Kibera, a densely populated urban slum in Nairobi, Kenya. Methods Surveillance was conducted among a monthly mean of 5,874 (range = 5,778-6,411) children <5 years old in two contiguous villages in Kibera. Participants had free access to the study clinic and their health events and utilization were noted during biweekly home visits. Patients meeting criteria for SARI (WHO-defined severe or very severe pneumonia, or oxygen saturation <90%) from March 1, 2007-February 28, 2011 had blood cultures processed for bacteria, and naso- and oro- pharyngeal swabs collected for quantitative real-time reverse transcription polymerase chain reaction testing for influenza viruses, parainfluenza viruses (PIV), respiratory syncytial virus (RSV), adenovirus, and human metapneumovirus (hMPV). Swabs collected during January 1, 2009 – February 28, 2010 were also tested for rhinoviruses, enterovirus, parechovirus, Mycoplasma pneumoniae , and Legionella species. Swabs were collected for simultaneous testing from a selected group of control-children visiting the clinic without recent respiratory or diarrheal illnesses. Results SARI overall incidence was 12.4 cases/100 person-years of observation (PYO) and 30.4 cases/100 PYO in infants. When comparing detection frequency in swabs from 815 SARI cases and 115 healthy controls, only RSV and influenza A virus were significantly more frequently detected in cases, although similar trends neared statistical significance for PIV, adenovirus and hMPV. The incidence for RSV was 2.8 cases/100 PYO and for influenza A was 1.0 cases/100 PYO. When considering all PIV, the rate was 1.1 case/100 PYO and the rate per 100 PYO for SARI-associated disease was 1.5 for adenovirus and 0.9 for hMPV. RSV and influenza A and B viruses were estimated to account for 16.2% and 6.7% of SARI cases, respectively; when taken together, PIV, adenovirus, and hMPV may account for >20% additional cases. Conclusions Influenza viruses and RSV (and possibly PIV, hMPV and adenoviruses) are important pathogens to consider when developing technologies and formulating strategies to treat and prevent SARI in children.